The problems posed by Alzheimer's disease (AD) mount while neither a cure nor reliable relief from symptoms lies within reach. Substantial evidence reveals amyloid plays a key role(s) in AD pathology, but recent human trials of amyloid-[unreadable] (A[unreadable]) immunotherapy suggest dementia involves more than senile plaque accumulation. The Oregon Brain Aging Study (OBAS) has revealed the existence of an oldest-old cohort (>85 years of age) who successfully maintain cognitive capabilities into advanced ages. Judged solely on histology, some of these non-demented oldest- old individuals exhibited brain pathology sufficient to result in an AD diagnosis, yet still retained undiminished mental abilities. These extensively characterized oldest-old OBAS participants present an extraordinary opportunity to compare and contrast the A[unreadable] profiles of the cognitively successful elderly to those of age-matched demented cases. Utilizing methods to isolate and characterize soluble as well as all deposited forms of A[unreadable] within the brain parenchyma and vasculature, including intra-membranous species, we will compare the detailed A[unreadable] molecular profiles of neuropathologically-assessed, non-demented oldest-old groups to those present in AD patients with dementia. Mass spectrometry analyses will enable us to compile in-depth rosters of the A[unreadable] spectrum existing within non-demented subjects, non-demented subjects exhibiting classic AD lesions (high pathology controls) and demented AD patients. Amyloid-[unreadable] precursor protein proteolysis patterns will be examined by Western blot experiments to reveal if amyloidogenic processing pathways are used to a lesser extent or employed at all in the non-demented aged compared to AD cases. Amyloid disruption therapy has shown great promise. Understanding which A[unreadable] species exhibit the greatest toxicity or the profiles most associated with dementia offers the prospect of more precise therapeutic interventions that both eliminate pathology while preserving cognitive capacity. PUBLIC HEALTH RELEVANCE: Recent clinical trials of Alzheimer's Disease (AD) therapies have been both encouraging and disappointing due to the discovery that while senile amyloid plaque deposits are removed, this alone is not able to cure dementia. Taking advantage of a program that systematically studies the oldest-old individuals who retain cognitive capacity to advanced ages, we will assess how these persons manage amyloid production and turnover while successfully avoiding dementia. This work will help to clarify which amyloid species or accumulation patterns are most associated with dementia and help to devise more precisely targeted therapies to stop AD emergence.